Regulation of the number of insulin receptors on the cell surface plays a critical role in determining insulin sensitivity. Previously, we have demonstrated that the insulin receptor is regulated at the transcriptional level by glucocorticoids. In order to study the mechanism of transcriptional regulation of the insulin receptor gene, we have cloned the 5' end of the human and mouse insulin receptor gene. We have begun to characterize the proximal promoter and find it has many features of a "housekeeping gene". We have localized a weak enhancer upstream of the promoter that is conserved in both the human and mouse promoters. This enhancer sequence binds nuclear proteins from any difference cell lines. The proximal promoter is probably responsible for the low level expression of the insulin receptor gene which occurs in most cell types. Recently we have identified a region of the first intron which may be involved in tissue specific regulation. This region seems to be responsible for the 10-fold induction of the insulin receptor gene during adipocyte differentiation. Further studies to identify sequences responsible for the transcriptional regulation are underway.